Neuropathic pain is caused by, for example, injury or dysfunction in a peripheral or central nervous system, and is intractable pain for which opioid receptor agonists such as morphine are not sufficiently effective. Disorders with neuropathic pain include disorders that exhibit hyperalgesic or allodynic symptoms, such as postherpetic neuralgia, trigeminal neuralgia, diabetic neuralgia, and persistent postoperative or posttraumatic pain.
Known analgesics that have hitherto been used in conventional drug treatment include centrally acting opioid receptor agonists such as morphine and non-steroidal anti-inflammatory drugs (NSAIDs) such as indomethacin. However, it is known that these analgesics generally have only a small effect on neuropathic pain, and that the effects provided by analgesics which work well for ordinary nociceptive pain (particularly, narcotic analgesics, etc.) are especially small. The inadequate analgesic effect provided by narcotic analgesics on neuropathic pain is regarded as a major characteristic of neuropathic pain. In some cases, the diagnosis of neuropathic pain is carried out using this characteristic.
Various factors are considered to be intricately involved in the onset of neuropathic pain. Conventionally known treatment methods for neuropathic pain include neurosurgical intervention such as nerve blocking and spinal epidural stimulation, and the lumbar intrathecal administration of drugs such as tricyclic antidepressants and baclofen. However, these treatment methods are either not sufficiently effective or have side effects. As an external preparation, capsaicin cream, which depletes the pain-producing substance P released from the nerve endings and thus alleviates pain, has been reported to be effective for postherpetic neuralgia and postmastectomy pain syndrome. However, due in part to the burning pain caused by capsaicin, the use of capsaicin cream has problems in terms of usefulness and safety. As can be seen, neuropathic pain is an intractable disorder for which an effective method of treatment has yet to be established.
Benzodiazepine receptors are classified into central benzodiazepine receptors and peripheral benzodiazepine receptors. Currently, peripheral benzodiazepine receptors (PBR) are recognized to be present in the central nervous system, and have been found to be present at a high density which is equal to, or higher than, the density of the central benzodiazepine receptors (CBR) present in the same region. Recent studies have reported that peripheral benzodiazepine receptors are present in microglia cells in the brain and are increased by psychoneurotic disorders, such as Alzheimer's disease and the like, by which microglia is activated in the brain.
Animal experiments have shown that peripheral benzodiazepine receptors in peripheral tissues such as adrenal cortex and the like are increased by stress or anxiety, but are, conversely, decreased when the stress is repeated (Drugan, R. C. et al.: Pharmacol. Biochem. Behav., 24:1673-1677, 1986). It has been reported that humans provide substantially the same results when examined with platelets (Gavish, M. et al.: Phamacol. Rev., 51:629-650, 1999). Thus, it is considered that a peripheral benzodiazepine receptor is deeply involved in stress. Recently, an increase in the expression level of PBR in ganglion of the posterior root of spinal nerve of a neuropathic pain model rat has been reported (Eur. J. Neurosci. 20:671 (2004)).
PK11195 (1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxyamide) is a compound developed by Rhone Poulenc Santa, and is known as a substance having a specific antagonistic action (antagonist) on peripheral benzodiazepine receptors (PBR). Conventionally, PK11195 is labeled with 11C, 18F, 123I or the like and used for determining the position of PBR in human heart or brain. PK11195 has been reported to be useful for diagnosing brain glioma or Alzheimer's disease when labeled with 11C. Japanese Patent Application (Published Japanese Translation of PCT International Publication) No. 2002-516279 (patent document 1) describes that PK11195 is a ligand bindable to a peripheral benzodiazepine receptor with high affinity and is useful for treating an inflammatory state of mammals.
Based on the report that the peripheral benzodiazepine receptor is involved in cell proliferation and that the expression thereof in tumor in human asteroid cells is related to tumor grade and proliferation index, Japanese Laid-Open Patent Publication No. 2003-508343 (patent document 2) describes that PK11195 is a composition usable for prophylaxis, diagnosis, recuperation and treatment of cancer as a substance for decreasing or inhibiting the actions of peripheral benzodiazepine receptors (PBR).
However, PK11195, which is a peripheral benzodiazepine receptor (PBR) antagonist, has not been described in any document as being effective for treating neuropathic pain.